1-Alkyl-2-(pyridylthiomethyl)-5-nitro-imidazoles and derivatives thereof as well as process for their manufacture

ABSTRACT

This invention provides 1-alkyl-2-(pyridylthiomethyl)-5-nitroimidazoles and 1-alkyl-2-(N-oxy-pyridylthiomethyl)-5-nitroimidazoles of the formula   in which R is methyl, ethyl or hydroxyethyl and the pyridyl and N-oxy-pyridyl group is linked in 2-, 3- or 4-position to the sulfur atom, as well as process for the manufacture of these compounds. The novel compounds are suitable for the treatment of protozoal diseases in mammals.

United States Patent [191 Winkelmann et al.

[ Sept. 23, 1975 l-ALKYL-2-(PYRIDYLTHIOMETI'IYL)-5- NITRO-IMIDAZOLES AND DERIVATIVES THEREOF AS WELL AS PROCESS FOR THEIR MANUFACTURE [75] Inventors: Erhardt Winkelmann, Kelkheim;

Wolfgang Raether, Dreieichenhain, both of Germany [73] Assignee: Hoechst Aktiengesellschaft, Frankfurt am Main, Germany 22 Filed: May 16, 1974 21 Appl. No.: 470,666

[30] Foreign Application Priority Data UNITED STATES PATENTS 3,635,995 1/1972 Manningm. 260/294.8 G

Primary Examiner-Henry R. Jiles Assistant ExaminerBernard l. Dentz Attorney, Agent, or Firm-Curtis, Morris & Safford [57] ABSTRACT This invention provides l-alkyl-2-(pyridylthiomethyl)- 5nitro-imidazoles and l-alkyl-2-(N-oxypyridylthiomethyl)-5-nitro-imidazoles of the formula in which R is methyl, ethyl or hydroxyethyl and the pyridyl and N-oxy-pyridyl group is linked in 2-, 3- or 4-position to the sulfur atom, as well as process for the manufacture of these compounds.

The novel compounds are suitable for the treatment of protozoal diseases in mammals.

19 Claims, No Drawings l-ALKYL-2-(PYRIDYLTHIOMETHYL)-5-NITRO- IMIDAZOLES AND DERIVATIVES THEREOF AS WELL AS PROCESS FOR THEIR MANUFACTURE in which R stands for a methyl, ethyl or hydroxyethyl group, and the pyridyl or N-oxy-pyridyl group is linked in 2-, 3- or 4-position to the sulfur atom.

The novel compounds have a pronounced activity against trichomonads and amebae, which activity is superior to the said Metronidazol.

Further object of this invention is a process for the manufacture of l-alkyl-2-(pyridylthiomethyl)-5-nitroimidazoles and lalkyl-2-(N-oxy-pyridylthiomethyl)-5- nitro-imidazoles of formula I, which comprises (a) reacting a l-alkyl-2-halomethyl-5-nitro-imidazole of the formula II I N -cH,-x u

in which R is defined as above, and X stands for a halogen atom, an acyloxy group, preferably acetoxy,

propoxy, butoxy, benzoyloxy, benzyloxy or tolyloxy, or an arylsulfonic acid ester group, preferably a benzenesulfonic acid ester, toluenesulfonic acid ester or naphthalene-sulfonic acid ester group, with a mercaptopyridine or a mercapto-N-oxy-pyridine or the alkali metal or ammonium salt thereof, corresponding to the formula III:

Y- 5Q (Ill) N (t) O in which Y stands fora hydrogen atom or an alkali metal or ammonium ion, or i b. reacting a l-alkyI-Z-mercaptomethyl-S-nitroimidazole of the formula IV -cH,-s-Y N O,N l

in which R and Y are defined as above, with a halogenopyridine or a halogeno-N-oxy-pyridine of the formulaV in which X is defined as above.

As compounds of the formula II, l-methyl-2- chloromethyl-S-nitro-imidazole, l-methyl-2- bromomethyl-S-nitro-imidazole, l-methyl-2-iodomethyl-S-nitro-imidazole, l-ethyl-2-chloromethyl-5-nitroimidazole, 1-ethyl-2-bromomethyl-5-nitro-imidazole, 1-ethyl-2-iodomethyl-5-nitro-imidazole, l-( 2- hydroxyethyl)-2-chloro-methyl-5-nitro-imidazole, l- (2-hydr0xyethyl)-2-br0momethyl(2-hydroxyethyl)-2- chloro-methyl-S-nitro-imidazole and l-(2- hydroxyethyl)-2-iodomethyl-5-nitro-imidazole or the corresponding methyl-Z-phenylor -2-toluyl-sulfonates are preferably used.

As compounds of the formula III, 2-, 3- or 4- mercaptopyridine as well as 2-, 3- or 4-mercapto-N- oxy-pyridine or the alkali metal or ammonium salts thereof are preferably used.

Instead of the mercapto compounds, compounds which yield mercaptanes, for example isothiouronium salts, may also be used.

As compounds of the formula IV, l-methyl-, l-ethylor l-( 2-hydroxyethyl )-2-mercaptomethyl-5-nitroimidazoles or the alkali metal or ammonium salts thereof are preferably used.

Instead of the mercapto compounds, compounds which yield mercaptanes, for example isothiouronium salts, may also be used.

As compounds of the formula V, 2-, 3-, 4-chloropyridine, 2-, 3-, 4-bromo-pyridine or 2-, 3-, 4-iodopyridine as well as 2-, 3-, 4-chloro-N-oxy-pyridine, 2-, 3-, 4-bromo-N-oxy-pyridine, 2-, 3-, 4-iodo-N-oxypyridine or the corresponding benzeneor toluenesulfonic acid esters are preferably used.

The reactions are advantageously carried out in equimolar amounts of the reactants in a solvent or dispersing agent. Depending on the mode of operation, an unpolar or polar aprotic solvent is used. As unpolar solin the range of from l to l50C. The reaction times are in the range of from a few minutes to several hours,

depending on the mode of operation.

When the free mercapto compounds of formulae Ill and IV areused, it is advantageous to use an acidbinding agent, for example a base, such as triethylamine or pyridine, or an alkali metal or alkaline earth metal carbonate or bicarbonate, hydroxide or alkoxide, for example alkali metal or alkaline earth metal methoxide, ethoxide or butoxide.

- v The products of the invention are isolated by usual methods, depending on the mode of operation, either by distillation of the solvents used or by dilution of the- The tested substance'was judged on the concentra-.

' tion of infective agentsito be found in the peritoneal exudate on the 6th day after infection. For' this purpose,

the concentration of infective agents established with the tested composition was compared with that of the comparison preparation and-of the infection control. The scheme, according to which the tested substance and the standard were judged with-regard=toithe concentration of 'infectants established, was the. following:

inefi'ective: Concentration of infective agents was not substantially reduced as compared to infection control.

Entamoeba histolytica. The novel products of the in- 'vention may be administered by the oral or local route.

For the oral administration, the products are generally made into tablets or capsules containing, per daily dosage unit, about 10 to 750 mg of the active-ingredient, in admixture with a usual diluent and/or excipient', for example starch, lactose, finely divided silicic acid, talcum, magnesium stearate or calcium carbonate. For a local or topical application, jellies, creams, ointments or suppositories may be used.

In addition to a good compatibility, the compounds of the invention are distinguished by a safe activity against trichomonads'and amebae invivo, which activity is substantially superior to the known pharmaceutical composition Metronidazol, as can be seen from the following Tables. v

The following Examples illustrate the invention.

EXAMPLE 1 (test for activity) Activity against Trichomonas foetus was generally tested on home-bred albino. mice (NMRl-strain) of both sexes.- The body weight of each animal was from 10 to 12 grams.

The substance to be tested was administered orally by means of an oesophagal sound either in an aqueous solution or, in the case of sparingly water-soluble compounds, in a Tylose suspension. The overall dosage was administered in two units, the first two hours prior to infection and the second two hours after infection. 4 Mice were used for each substance to be tested and for each dosage. I q q Infection was brought about by intraperitoneal injection of 19 million infective agents per animal in a suspension in 0.5 ml of a culture medium, Merck I. The comparison preparation Metronidazol was administered by the same route and in the same dosage asthe substance to betested (see Table l). I

As infection controls there were generally used 10 mice which, after infection, were not treated any more. Another 5 mice served as a zero control, that is to say, these animals were neither treated not infected.

Six days after infection, all the test animals were killed and'the peritoneal exudate was examined for trichomonads. Mice which had died before were subjected to the same examination.

Judgementz3; 4-

a. faint: Concentration .of infective agents was moderately reduced compared with infection control. Judgement: 2 v

b. unsatisfactory: Concentration of infective agents was substantially reduced compared with infection control. Judgement: l

I c. no infective agents found. Judgement: 0

TABLE 1 Composition dosage in trig/kg concentration of mouse, per os infectant Trichomonas -foetusin-4 mice l" ZXlOO' 0000 ';2 50 0000 z x 2 5 0 0 0 .0 2 X l2.5 0 0 0 0 ll 2x100 v.0000 2 x 50 0'00 0 2X25 2022 2 'l2.5. 4344 infection controls r 'rbduci of the invention: l-rnethyl-2 (.2'- pyridylthiomethyl)-5-nitro-imidazole [I comparative composition: Metronidazol EXAMPLE 2 (test for activity) Activity against Entamoeba histolytica was generally tested on cross-bred golden hamsters of both sexes. The body weight of each animal was generally in the range of from S0 to 60 grams.

The substance to be tested was administered orally by meansof an oesophagal sound, eitherin an aqueous solution or, in thecase ofv paringly water-soluble compounds, in a Tylose-suspension. The overall dosage was administered in four. units, the first two hours pr ior to infection, the second 2 hours after infection, the third one day after infection and the fourth 2 days after infection. 4 Hamsters were used for each substance to be tested, .j 1

Infection was brought about by intrahepatic injection of 130,000 infective agents per animal as a suspension in 0.1 ml of 'ITY medium (E. hist.-Crithida culture). The standard Metronidazol was administered by the same route and in the same dosage as the substance to be tested (see Table 2).

As infection controls there were generally used 10 hamsters which were, after infection, not treated any more. Another 5 hamsters served as a zero control, that is to say, these animals were neither treated nor infected. a

Six days at the earliest and 8 days at the latest after infection, all the animals were killed. Subsequently, the state of the liver was judged according to the degree of icteric' necrosis developed. Hamsters which had died during the period of infection were subjected to the same examination. I

The observations on the state of the liver obtained with the tested composition and with the standard were compared with those' of the infection controls. The scheme, according to which the liver findings (with tested composition and standard) were judged, was the following? A ineffective: lcteric necrosis did'not show any substantial difference from that of infection controls. Possible judgement: '3; 4' (in rare cases: 2),

effective: 1

a. faint: lcteric necrosis was less developed than with the infection controlsq" Possible judgement: frequently 2 (in rare cases: 1), i

b. unsatisfactory: lcteric necrosis was substantially reduced as compared to infection controls. Possible judgement: (in'rare cases), predominantly 1; 2 (in rare cases), i v

0. good: no icteric necrosis was discovered." Judgement: 0 p v p fl TABLE 2 composition dosage in mg/kg liver findings golden hamster, per os Entamoeba histolytica (extraintestinaD in 4 golden hamsters 4 X 100 L j 0 0 0 0 4 x 50 0 0 0 0 4 x 25 0 0 0 0 4 X 100. 0 0 0 0 4 X 50 0 1 0 0 4 X 25 2 0 2 0 infection 1 g controls 4 4 4 4 I Product of the invention; 1-methy1-2-(2'- pyridylthiomethyl 5-nitro"-imidazole ll= comparative composition: Metronidazol EXAMPLE 3 (preparation of active substances) 1. l-Methyl-2-( 2 -pyridylthiomethyl -5-nitroimidazole 2.3 Grams(0.1 mol) of metallic sodium were dissolved in small portions in 50 ml of anhydrous methanol. into this sodium methylate solution, 11.0 g (0.1 mol) of Z-mercaptopyridine dissolved in 70 ml of anhydrous methanol were introduced and the solution was evaporated in vacuo. A solution of 17.55 g (0.1 mol) of 1-methyl-2-chloromethyl-S-nitro-imidazol in 100 ml of dimethylacetamide was added to the residue, and the reaction mixture was heated to 110C for 1 hour. After cooling, water was added to the solution until crystallization began. The end product was suctionfiltered and recrystallized from ethanol with the addition of charcoal. 20.0 Grams of l-methyl-2-(2'- pyridylthiomethyl)-5-nitro-imidazole were thus obtained (corresponding to 80 of the theoretical yield) in the form of yellowish crystals, mp. 147C. In the same manner there were obtained, with good yields,

2. 1-Methyl-2-( 3 '-pyridy1thiomethyl )-5-nitroimidazole from 1-methyl-2-chloromethyl-5-nitroimidazole and B-mercaptopyridine.

3. 1-Methyl-2-(4-pyridylthiomethy1)-5-nitroimidazole (m.p. 143C) from 1-methyl-2chloromethyl-5-nitro-imidazole and 4-mercapto-pyridine.

4. 1 Methyl-24 N-oxy-2 '-pyridylthiomethyl )5 -nitroimidazole (m.p. 257C with decomposition) from 1- methyl-2-chloromethyl-S-nitro-imidazole and 2mercaptopyridyl-N-oxide.

5. l -Methyl-2-( N-oxy-3 -pyridylthiomethyl 5 -nitroimidazole from 1-rnethyl-2-chloromethyl-5-nitroimidazole and 3-mercaptopyridyl-N-oxide.

6. 1-Methyl-2-(N oxy4'-pyridylthiomethyl)-5-nitroimidazole (m.p. 250C with decomposition) from 1- methyl-2-chloromethyl-S-nitro-imidazole and 4-rnercaptopyridyl-N-oxide.

7. 1-Ethyl-2-(2-pyridylt.hiomethyl)=5-nitroimidazole (m.p. 68C) from 1-ethyl-2-chloromethyl-5 nitro-imidazole'and Z-niercaptopyridine. 8. 1-Ethyl-2-( 3 -pyridylthiomethyl)-5-nitroimidazole from l-ethyl-Z; -chloromethyl-5-nitro imidazole and 3-mercaptopyridine. I

9. 1-Ethyl-2-(4 pyridylthiomethyl)-5-nitroimidazole (m.p. 64C) from 1-ethyl-2-chloromethyl-5- nitro imidazole and 4-mercapto-py ridine. r

10. 1-ethyl-2 (N-oxy-2epyridylthiomethyl)-5-nitroimidazole (m.p. 176C) from 1-ethyl-2-chloromethyl- S-nitro-imidazole and 2-mercaptopyridyl-N-oxide.

1 1. 1 -Ethyl-2-( N-oxy-3 -pyridylthiomethyl )-5-nitroimidazole from 1-ethy1-2-chloromethyl-5-nitroimidazole and 3-mercapto-pyridyl-N-oxide.

l2. 1 Ethyl-2-(N-oxy-4'-pyridylthiomethyl)-5-nitroimidazole (m.p. 167C) from l-ethyl-2-chloromethyl- 5-nitro-imidazole and 4-mercaptopyridyLN-oxide.

13 l-(2 Hydroxyetliyl)-2-(2'-pyridylthiomethyl)-5- nitroimidazole (m.p. C) from l-(2-acetoxyethyl)- 2- chloromethyl-5-nitro-imidazole and 2- mercaptopyridine with subsequent saponification of the acetyl group.

14. l'(2-Hydroxyethyl) 2-(3'-pyridylthiomethyl)-5- nitroimidazole from 1-(2-acetoxyethyl )-2-chloromethyl-S-nitroimidazole and 3-mercaptopyridine and subsequent saponification of the acetyl group.

15. 1-(2-l-lydroxyethyl) 2(4'-pyridylthiomethyl)-5- nitroimidazole (m.p. 98C) from 1-(2-acetoxyethyl)-2- chloromethyl-S nitro-imidazole and 4-mercaptopyridine and subsequent saponification of the acetyl group.

16. 1-(2-Hydroxyethyl)-2-(N-oxy-2-pyridylthiomethyl)'-'5-nitro-imidazole from 1 -(2-acetoxyethyl)-2-' chloromethyl-S-nitro-imidazole and Z-mercaptopyridyl-N-oxide and saponification of the acetyl group.

17. 1-( 2-l-1ydroxyethyl )-2-(N-oxy-3 '-pyridylthiomethyl)-5-nitro-imidazole from 1-(2-acetoxyethyl)-2- chloromethyl-S-nitro-imidazole and 3-mercaptopyridyl-N-oxide and saponification of the acetyl group.

18. 1-( 2-Hydroxyethyl )-2-(N-oxy-4'-pyridy1thiomethyl)-5-nitro-imidazole from 1-(2-acetoxyethyl)-2- chloromethyl)-5-nitro-imidazole and 4-mercaptopyridyl-N-oxide and saponification of the acetyl group.

PREPARATION OF THE STARTING SUBSTANCES The 1-a1ky1-2-chloromethyl-5-nitro-imidazoles used as starting substances were prepared according to known methods by reacting 1-alkyl-2-hydroxymethyl S-nitro-imidazoles with thionyl chloride.

19. 26.1 Grams (0.1 mol) of 1-methy1-2- benzoyloxymethyl-S-nitro-imidazole were dissolved while stirring in ml of dimethylformamide; then 11.1 g (0.1 mol) of Z-mercaptopyridine and 13.8 g of potash (free from water and powdered) were added. A very faintly exothermic reaction was perceptible only.

The reaction mixture was heated to 80C for 1 hour,

' whereupon the color of the mixture changed from yellow toward light brown and a white precipitate formed. The mixture was then cooled to room temperature and the end'product was precipitated by stirring it into about 500 ml of ice water. The product was suctionfiltered, thoroughly washed with water and recrystallized from about 3000 ml of isopropanol. 18.0 Grams (72 of the theoretical yield) of 1-methyl-2-(2- pyridylthiomethyl)--nitro-imidaz0le were obtained as a faintly yellow crystallized powder, m.p. 146-147C.

The 1-methyl-2-benzoyloxymethyl-5-nitro-imidazole used as starting material was prepared by reacting 1- methyl-2-hydroxy-methyl-S-nitro-imidazole with benzoyl chloride in the presence of a hydrogen chloridebinding agent, such as, for example pyridine, mp. 108C.

20. The reaction of equimolar amounts of l-methyl- 2-(S-isothiouronium-methyl)-5-nitro-imidazole hydrochloride and 2-bromo-pyridine in dimethylformamide in the presence of 2 molar equivalents of sodium methylate with stirring for 1 hour at room temperature yielded 1-methyl- 2-( 2-pyridylthiomethyl )-5-nitroimidazole, mp. 147C. 1

The 1-methyl-2( S-isothiouronium-methyl)-5- nitroimidazole hydrochloride used as starting material was used instead of the free, unstable 1-methyl-2- mercaptomethyl-S-nitro-imidazole as a possible mercaptane-forming agent. The preparation of l-methyl-2- (S-isothiouroniummethyl)-5-nitro-imidazole hydrochloride from 1 -methyl-2-chloromethyl-5-nitroimidazole and thiourea has been disclosed in German Offenlegungsschrift No. 2,124,103 (cf. Merck lnc., Rahway).

We claim:

1. A compound of the formula in which R stands for a methyl, ethyl or hydroxyethyl group, n is 0 or 1, and the pyridyl or N-oxy-pyridyl group is linked in 2-, 3- or 4-position to the sulfur atom.

2. A compound of claim 1, which is l-methyl-2-(2- pyridylthio-methyl)-5-nitro-imidazole.

3. A compound of claim 1, which is 1-methy1-2-(3'- pyridylthio-methyl)-5-nitro-imidazole. 1 i

4. A compound of claim 1, which is l,-methyl-2-(4- pyridylthio-methyl)-5-nitro-imidazole.

5. A compound of claim 1, which is 1-methyl-2-(N- oxy-2 '-pyridyl-thiomethy1)-5 -nitro-imidazole.

6. A compound of claim 1, which is l-methyl-Z-(N- oxy-3 '-pyridyl-thiomethyl )-5-nitro-imidazole.

7. A compound of claim 1, which is 1-methyl-2-(N- oxy-4-pyridyl-thiomethyl)-5-nitro-imidazole.

8. A compound of claim 1, which is 1-ethyl-2-(2'- pyridylthiomethyl)-5-nitro-imidazole.

9. A compound of claim 1, which is 1-ethyl-2-(3'- pyridylthiomethyl)-5-nitro-imidazole.

10. A compound of claim 1, which is l-ethyl-2-(4'- pyridylthiomethyl)5-nitro-imidazole.

11. A compound of claim 1, which is l-ethyl-2-(N- oxy-2-pyridylthiomethyl)-5-nitro-imidazole.

12. A compound of claim 1, which is 1-ethy1-2-(N- oxy-3'-pyridylthiomethyl)-5-nitro-imidazole.

13. A compound of claim 1, which is l-ethyl-Z-(N- oxy-4-pyridylthiomethyl)-5-nitro-imidazo1e.

14. A compound of claim 1, which is 1-(2- hydroxyethyl)-2-(2'-pyridylthiomethyl)-5-nitroimidazole.

15. A compound of claim 1, which is hydroxyethy1)'-2-(3 '-pyridylthiomethyl )-5 -nitroimidazole.

16. A compound of claim 1, which is hydroxyethyl)-2-(4-pyridylthiomethyl)-5-nitroimidazole.

17. A compound of claim 1, which is 1-(2- hydroxyethy1)-2-(N-oxy-2 -pyridylthiomethyl )-5-nitroimidazole.

18. A compound of claim 1, which is 1-(2- hydroxyethyl)-2-(N-oxy-3-pyridylthiomethyl)-5 nitroimidazole.-

19. A compound of claim 1, which is 1-(2- hydroxyethyl)-2-(N-oxy-4'-pyridylthiomethyl)-5-nitroimidazole. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, which is 1-methyl-2-(2''-pyridylthio-methyl)-5-nitro-imidazole.
 3. A compound of claim 1, which is 1-methyl-2-(3''-pyridylthio-methyl)-5-nitro-imidazole.
 4. A compound of claim 1, which is 1-methyl-2-(4''-pyridylthio-methyl)-5-nitro-imidazole.
 5. A compound of claim 1, which is 1-methyl-2-(N-oxy-2''-pyridyl-thiomethyl)-5-nitro-imidazole.
 6. A compound of claim 1, which is 1-methyl-2-(N-oxy-3''-pyridyl-thiomethyl)-5-nitro-imidazole.
 7. A compound of claim 1, which is 1-methyl-2-(N-oxy-4''-pyridyl-thiomethyl)-5-nitro-imidazole.
 8. A compound of claim 1, which is 1-ethyl-2-(2''-pyridylthiomethyl)-5-nitro-imidazole.
 9. A compound of claim 1, which is 1-ethyl-2-(3''-pyridylthiomethyl)-5-nitro-imidazole.
 10. A compound of claim 1, which is 1-ethyl-2-(4''-pyridylthiomethyl)-5-nitro-imidazole.
 11. A compound of claim 1, which is 1-ethyl-2-(N-oxy-2''-pyridylthiomethyl)-5-nitro-imidazole.
 12. A compound of claim 1, which is 1-ethyl-2-(N-oxy-3''-pyridylthiomethyl)-5-nitro-imidazole.
 13. A compound of claim 1, which is 1-ethyl-2-(N-oxy-4''-pyridylthiomethyl)-5-nitro-imidazole.
 14. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(2''-pyridylthiomethyl)-5-nitro-imidazole.
 15. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(3''-pyridylthiomethyl)-5-nitro-imidazole.
 16. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(4''-pyridylthiomethyl)-5-nitro-imidazole.
 17. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(N-oxy-2''-pyridylthiomethyl)-5-nitro-imidazole.
 18. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(N-oxy-3''-pyridylthiomethyl)-5-nitro-imidazole.
 19. A compound of claim 1, which is 1-(2-hydroxyethyl)-2-(N-oxy-4''-pyridylthiomethyl)-5-nitro-imidazole. 